GENETIC STUDIES OF OCULAR ANGIOGENESIS

血管生成，即新血管的形成，是由内源性血管生成刺激剂与抑制剂的局部平衡决定的严格调节的功能。 这个提议的中心假设是，血管生成平衡在个体之间变化，并且这种变化在很大程度上是由遗传决定的。事实上，流行病学数据表明，不同种族人群对眼部新生血管的易感性不同。我们已经调查了近交系小鼠品系，以了解小鼠是否具有一系列模拟人类的血管生成多样性。令人惊讶的是，我们发现了一个大范围的血管生成的反应，小球的碱性成纤维细胞生长因子（bFGF）植入不同菌株的角膜。最低响应和最高响应之间的差异是1200%。到目前为止，最敏感的品系是一种称为129的白化病小鼠。在该品系中，与具有中度角膜血管生成且无虹膜新血管生成的C57黑小鼠相比，角膜bFGF颗粒诱导非常侵袭性的角膜和虹膜新血管生成。 有趣的是，129只小鼠的酪氨酸酶阳性亚株（其是色素沉着的）保留了过度侵袭性的角膜新生血管反应，但没有虹膜新生血管形成。为了评估这129只小鼠的侵袭性角膜血管生成反应，我们建议将它们与其他反应较低的近交系小鼠交配。然后，我们将描述杂交后代的血管生成表型，并将使用遗传作图来确定与该表型分离的染色体位点。如果该区域存在候选基因，则将筛选这些基因的DNA序列改变。本建议的目的是表征不同小鼠近交系的血管生成表型，并确定这些表型的遗传贡献。 在小鼠中识别控制眼部血管生成的基因将有助于在人类中发现类似的基因，其特征可能提示新的治疗新生血管性青光眼和黄斑变性中所见的病理性新生血管形成的新疗法。

Angiogenesis, the formation of new blood vessels, is a tightly regulated function determined by the local balance of endogenous angiogenesis stimulators versus inhibitors. The central hypothesis for this proposal is that the angiogenic balance varies between individuals and that this variation is in large part genetically determined. Indeed, epidemiological data suggests that different racial populations have varied susceptibility to ocular neovascularization. We have surveyed inbred mouse strains to see if mice have a range of angiogenic diversity that models that of humans. Surprisingly, we found a large range of angiogenic responses to pellets of basic fibroblast growth factor (bFGF) implanted in the corneas of different strains. The difference between the lowest response and the highest response was 1200 percent. To date, the most sensitive strain is an albino mouse known as 129. In this strain, corneal bFGF pellets induce very aggressive corneal and iris neovascularization as compared to C57 black mice which have moderate corneal angiogenesis and no iris neovascularization. Interestingly, tyrosinase positive substrains of 129 mice (which are pigmented), retain the overly aggressive corneal neovascular response but do not have iris neovascularization. To evaluate the aggressive corneal angiogenic response of the 129 mice we propose to breed them with other inbred strains with lower responses. We will then characterize the angiogenic phenotype of the offspring of the crosses and will use genetic mapping to identify the chromosomal locus that segregates with this phenotype. If there are candidate genes in the region, these will be screened for alterations in DNA sequence. The goal of this proposal is to characterize the angiogenic phenotypes of different murine inbred strains and to identify the genetic contributions to these phenotypes. Identifying the genes controlling ocular angiogenesis in mice will help find similar genes in humans, the characterization of which may suggest new therapies for pathologic neovascularization seen in neovascular glaucoma and macular degeneration.